Derivatives of pyrazolo(3,4-b)thieno(2,3-d)pyridine-2-carboxylic acids

ABSTRACT

New derivatives of pyrazolo(3,4-b)thieno(2,3-d)-pyridene-2carboxylic acids have the general formula   They are useful as antiinflammatory agents and central nervous system depressants. In addition, this type of compound increases the intracellular concentration of adenosine-3&#39;&#39;,5&#39;&#39;-cyclic monophosphate.

United States Patent [191 Denzel et al.

[ June 3, 1975 Hoehn, Tegemheim, both of Germany [73] Assignee: E. R.Squibb & Sons, Inc.,

Princeton, NJ.

22 Filed: Sept. 28, 1973 211 Appl. No.: 401,798

[52] US. Cl. 260/294.8 B; 260/294.8 C;

260/295.5 B; 260/310 R [51] Int. Cl C07d 31/50 [58] Field of Search260/294.8 B

[56] References Cited UNITED STATES PATENTS 3,787,430 1/1974 Hoehn etal. 260/296 H Primary Examiner-Alan L. Rotman Attorney, Agent, orFirmLawrence S. Levinson; Merle J. Smith [5 7] ABSTRACT New derivativesof pyrazolo[3,4-b]thieno[2,3-d]- pyridene-Lcarboxylic acids have thegeneral formula COOR sc They are useful as antiinflammatory agents andcentral nervous system depressants. In addition, this type of compoundincreases the intracellular concentration of adenosine-3 ,5 '-cyclic-monophosphate.

10 Claims, No Drawings DERIVATIVES OFPYRAZOLO(3,4-B)THIENO(2,3-D)PYRIDINE-2- CARBOXYLIC ACIDS SUMMARY OF THEINVENTION This invention relates to new pyrazolo[3,4-b]thieno[2,3-dlpyridine-Z-carboxylic acids and esters. These newcompounds have the general formula The symbols have the followingmeanings in formula I and throughout this specification.

R is hydrogen or lower alkyl.

R, is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl.

R is hydrogen or lower alkyl.

R is lower alkyl, phenyl or substituted phenyl, hydroxy or lower alkoxy,R can also be an acyclic basic nitrogen group wherein R R each ishydrogen or lower alkyl. R can also be a hydrazine,

or a hydrazone.

group, wherein R R and R each represents a hydrogen, lower alkyl orphenyl. R represents each of said groups other than hydrogen. R ishydrogen, lower alkyl or phenyl.

The lower alkyl groups referred to throughout this specification includestraight or branched chain hydro-v carbon groups containing 1 to 7carbon atoms, preferably l to 4 carbons. Examples of the type of groupscontemplated are methyl, ethyl, propyl, isopropyl etc. The lower alkoxygroups include such lower alkyl groups bonded to an oxygen, e.g.,methoxy, ethoxy, propoxy, isopropoxy, etc.

The substituted phenyl groups include one or two simple substituents,i.e., lower alkyl, halogen, (F. Cl, Br or I, preferably Cl or Br)trifluoromethyl, amino or carboxy.

Preferred embodiments of this invention are as follows:

R is hydrogen or lower alkyl, especially ethyl.

R, is hydrogen or lower alkyl, especially ethyl.

R is hydrogen or lower alkyl, especially hydrogen.

R is lower alkyl, phenyl, hydroxy, lower alkoxy, lower alkylamino,hydrazino or lower alkylhydrazino, lower alkylidenelydrazono, especiallylower alkyl, phenyl, hydroxy, lower alkoxy particularly ethoxy, and alsobutylamino, hydrazino and isopropylidene-hydrazono.

DETAILED DESCRIPTION OF THE INVENTION The new compounds of formula I areproduced by the following series of reactions:

A S-aminopyrazole of the formula [prepared according to the proceduredescribed in Z.f. Chemie 10, 386388 (1970)] is made to react with analkoxymethylene acid ester of the formula II (I 4 COOlower alkylalkyl--OC=C C0Olower alkyl by heating at a temperature of about C. Theresulting compound of the formula COOlower alkyl COOlower alkyl iscyclized in an inert organic solvent such as diphenyl ether at about 230to 260C, while distilling off the alcohol formed, producing a compoundof the formula This compound of formula V is halogenated by treatmentwith an inorganic acid chloride like phosphorus oxychloride, thionylchloride or the like, producing a compound of the formula (VI) c1COOlower alkyl R N N R HS-CH COOR (VII) a compound of the formula (VIII)8 CH -COOlower alkyl COOlower alkyl is produced.

On treatment with a base such as an alkali metal alcoholate like sodiumethoxide, or sodium hydride or potassium carbonate, the product offormula VIII undergoes cyclization forming a product of the formulaCOOlower alkyl (I A compound of the formula (Ib) COOl ower alkyl whereinR is lower alkoxy as in formula Ib is now produced by reaction of theproduct of formula Ia with a lower alkyl halide in the presence of abase like potassium carbonate.

A compound of the formula (Ic) O-lower alkyl S C 'l n R 5 R s \N 5 2 lll N N R wherein R is an amino group is formed on treatment of a compoundof formula Ib with the appropriate amine When using a hydrazine offormula 7 H2NN COO-lower alkyl S C [I C R R 2 7 l 1 .\N \R 40 l 4 with ahydrazino group is formed.

A compound of the formula COQ l0wer alkyl NHN= with a hydrazono group isnow produced by reaction of a hydrazine (R R =I-I) of formula Id withthe appropriate aldehyde or ketone of the formula When R in formula I islower alkyl or a phenyl group, such compounds are produced by reactionof a S-aminopyrazole of formula II with an alkoxymethylenebenzoyl oralkanoyl ester of the formula R COO-lower alkyl wherein R is loweralkyl, phenyl or substituted phenyl.

The resulting product of the formula R2 ll NH CH (IIa) wherein R is ahetero group like furfuryl, pyridyl, pyrimidyl or the like, is thestarting material.

This material is processed as described above: through the reaction withthe alkoxymethylene esters of formulas III and XI, cyclization of theproduct corre-- sponding to formulas IV and IVa, to obtain a compound offormula VI which is made to react with the mercaptoacetic esterproducing a compound of formula VIII which is cyclized to obtain acompound of the formula COOR wherein R is hydroxy, lower alkyl orphenyl. When R is alkyl or phenyl, these compounds are oxidized with anoxidizing agent like selenium dioxide in a high boiling solvent likediethyleneglycol dimethyl ether at about yielding the compound offormula I with hydrogen in the 1-position of the molecule.

When R is hydroxy, the compound is alkylated, yielding a product offormula COOR \ o-lower alkyl which is now oxidized as described above,producing a compound of formula Ib with hydrogen in the 1- position ofthe molecule. Compounds of formula Ic, d, 6 with hydrogen in the1-position, bearing amino, hydrazino and hydrazono groups, are nowproduced in the same manner as described above.

The free acids, i.e., R is hydrogen, are obtained from the esters byhydrolysis, e.g., by treatment with alcoholic sodium hydroxide solution.

The new compounds of this invention have antiinflammatory properties andare useful as antiinflammatory agents, for example, to reduce localinflammatory conditions such as those of an edematous nature orresulting from proliferation of connective tissue in various mammalianspecies such as rats, dogs and the like when given orally in dosages ofabout 5 to 50 mg/kg/day, preferably 5 to 25 mg/kg/day, in single or 2 to4 divided doses, as indicated by the carageenan edema assay in rats. Theactive substance may be utilized in compositions such as tablets,capsules, solutions or suspensions containing up to about 300 mg. perunit of dosage of a compound or mixture of compounds of formula I. Theremay be compounded in conventional manner with a physiologicallyacceptable vehicle or carrier, excipient, binder, preservative,stabilizer, flavor, etc. as called for by accepted pharmaceuticalpractice. Topical preparations containing about 0.01 to 3 percent byweight of active substance in a lotion, salve or cream may also be used.

The new compounds of the invention also have central nervous systemdepressant activity and can be used as tranquilizers or ataractic agentsfor the relief of anxiety and tension states, for example, in mice,cats, rats, dogs and other mammalian species, in the same manner aschlordiazepoxide. For this purpose a compound or mixture of compounds offormula I is administered orally or parenterally in a conventionaldosage form such as tablet, capsule, injectable or the like. A singledose, or preferably 2 to 4 divided daily doses, provided on a basis ofabout 1 to 50 mg. per kilogram per day, preferably about 2 to 15 mg. perkilogram per day, is appropriate. These may be conventionally formulated.in an oral or parenteral dosage form by compounding about 10 to 250 mg.per unit of dosage with conventional vehicle, excipient, binder,preservative, stabilizer, flavor or the like as called for by acceptedpharmaceutical practice.

The new compounds also increase the intracellular concentration ofadenosine-3, 5'-cyclic monophosphate, and thus by the administration ofabout 1 to 100 mg/kg/day, preferably abouttlO to 50 mg/kg, in single ortwo to four divided doses in conventional oral or parenteral dosageforms such as those described above may be used to alleviate thesymptoms of asthma.

The following examples are illustrative of the invention. Alltemperatures are expressed on the Centigrade scale.

EXAMPLE 1 3-Ethoxy-6-ethyl-6H-pyrazolo[3,4-b]thieno[2,3-d]pyridine-Z-carboxylic acid a.[[(1-ethyl-5-pyrazolyl)aminolmethylenelmalonic acid diethyl ester 245 g.of l-Ethyl-S-aminopyrazole (2.2 mol.) and 476 g. of ethoxymethylenemalonic acid diethyl ester (2.2 mol.) are heated to 120 (bathtemperature) for 2 hours with stirring. The ethanol formed by thisreaction is removed by means of a water aspirator. Then vacuumdistillation (b.p. M l54l60) yields 520 g. (84%) of theory) ofl-ethyl-5-pyrazolyl)amino1methylenelmalonic acid diethyl ester as aquickly crystallizing oil, m.p. 5053.

The compound is recrystallized from N-hexane, m.p. 55'-57. Thehydrochloride salt is formed by treating the above product with diluteethanolic hydrogen chloride solution.

b. l-ethyl-4-hydroxyl H-pyrazolo[3 ,4-b]-pyridine-5- carboxylic acidethyl ester 253 g. of [[(1-Ethyl-5-pyrazolyl)amino]methylene]- malonicacid diethyl ester (0.09 mol.) are dissolved in 770 g. of diphenylether. The reaction mixture is heated to 235-250 (bath temperature) andallowed to react at this temperature for 1-2 hours while the resultingethanol is continuously distilled off. The last amount of alcohol isremoved by means of a water aspirator. The diphenyl ether is separatedby distillation with a fractionating column in vacuo. The1-ethyl-4-hydroxy-1H- pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethylester, is obtained at hp. 1l5-l20, yield 195 g. 92 percent of theory,m.p. 85-87. The compound is recrystallized from benzene (90l00), m.p.8789.

c. 4-chloro-l-ethyl-1H-pyrazolo[3,4-b]-pyridine-5- carboxylic acid,ethyl ester A mixture of 23.5 g. of l-ethyl-4-hydroxy-1H- pyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester, (0.1 mol.) and 150 ml. ofphosphorus oxychloride is refluxed for 4 hours. Then the excessphosphorus oxychloride is removed by vacuum distillation. As soon as thephosphorus oxychloride has been removed, the oily residue solidifies oncooling. It is treated with water and filtered under suction (24.5 g.),m.p. 55-60. The 4 chloro-l-ethyl-lH-pyrazolo[3,4-b1pyridine-5-carboxylic acid, ethyl ester is recrystallized from nhexane (22.5 g. 87percent), m.p. 62.

d. I-ethyl-4-(ethoxycarbonylmethyl )thiol H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester I 50.5 g. of4Chloro-l-ethyl-11-1-pyrazolo[3,4-b]- pyridine-S-carboxylic acid ethylester, (0.2 mol.) are dissolved in 200 ml. of dimethylformamide. 25 g.of triethylamine are added and 24 g. of mercaptoacetic acid ethyl esterare dropped in with stirring. Stirring is continued at 40 for 5 hours.After this time, the mixture is cooled and water is added. l-Ethyl-4-(ethoxycarbonylmethyl )thio-l H-pyrazolo[ 3 ,4- b]pyridine-5-carboxylicacid, ethyl ester, solidifies, is filtered off and recrystallized fromethyl acetate, yield 58 g. (86 percent), m.p. 62-63.

e. 6-ethyl-3-hydroxy-6H-pyrazolo[3,4-b]thieno-[2,3-

d]pyridine-Z-carboxylic acid ethyl ester 3.4 g. ofl-Ethyl-4-(ethoxycarbonylmethyl)thio-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, (0.01 mol.) and0.36 g. ofsodium hydride (0.015 mol.) are refluxed for 3 hours in drydioxane. The solution is acidified with acetic acid and evaporated todryness. The product, 6-ethyl-3-hydroxy-6H-pyrazolo[3,4-b]thieno[2,3-d]-pyridine-2-carboxylic acid ethyl ester is crystallizedwith water, filtered and recrystallized from DMF, m.p. l55l57, yield 2.5g. (79%).

f. 3-ethoxy-6-ethyl-6H-pyrazolo[ 3,4-b ]thieno[ 2,3-

d]pyridine-2-carboxylic acid, ethyl ester 1.45 g. of6-Ethyl-3-hydroxy-6H-pyrazolo[3,4-b]- thieno[2,3-d]pyridine-2-carboxylicacid, ethyl ester, (0.05 mol.), 1.4 g. of potassium carbonate (0.01mol.) and 1.55 g. of ethyl iodide (0.01 mol.) are suspended in 10 ml. ofdimethylformamide and stirred for 10 hours at 60. After this period, thesolid is filtered off and water is added to the filtrate,3-ethoxy-6-ethyl-6H- pyrazolo[3,4-b]thieno[2,3-dlpyridine-Z-carboxylicacid, ethyl ester, solidifies, is filtered off and recrystallized fromethyl acetate, m.p. 96, yield 1.1 g. (69%).

g. 3-ethoxy-6-ethyl-6H-pyrazolo[3,4-b]thieno[2,3-

d]pyridine-2-carboxylic acid 3,2 g. of 3-Ethoxy-6-ethyl-6H-pyrazolo[3,4-b]thieno-[2,3-d]pyridine-2-carboxylic acid, ethyl ester (0.01 mol.) istreated for 10 hours at 50 with a solution of 1 g. of potassiumhydroxidein 20 ml. of alcohol. The solvent is distilled off in vacuo,the residue is dissolved in 20 ml. of water and acidified with aceticacid. The 3-ethoxy-6-ethyl-6H-pyrazolo[3,4-b]thieno[2,3-d]pyridine-Z-carboxylic acid solidifies, is filtered off andrecrystallized from dimethylformamide, yield 2.1 g. (72 percent), m.p.23023l.

EXAMPLE 2 3-(Butylamino)-6-ethyl-6H-pyrazolo[3,4-b]thieno[2,3-dlpyridine-Z-carboxylic acid, ethyl ester 3.2 g. of3-ethoxy-6-ethyl-6H-pyrazolo[3,4- b]thieno[2,3-d]pyridine-2-carboxylicacid, ethyl ester, and 10 ml. of butylamine are refluxed 24 hours withstirring. The excess butylamine is removed in vacuo and the residue,3-(butylamino)-6-ethyl-6H-pyrazo1o[3,4-b]thieno[2,3-d]pyridine-2-carboxylic acid, ethyl ester isrecrystallized from methanol, yield 2.5 g. (72%), m.p. lO6-l08.

EXAMPLE 3 6-Ethyl-3-(isopropylidenehydrazino)-6H-pyrazolo[3,4-b]thieno-[2,3-dlpyridine-2-carboxylic acid, ethyl ester a.6-ethyl-3-hydrazino-6H-pyrazolo[3,4-b]thieno-[2,3-d]pyridine-2-carboxylic acid ethyl ester 3.2 g. of3-ethoxy-6-ethyl-6H-pyrazolo[3,4-b]thien0- [2,3-dlpyridine-Z-carboxylicacid, ethyl ester (0.01 mol.) and 10 ml. of hydrazine hydrate arerefluxed with 5 ml. of butylalcohol for 24 hours. The solvent and theexcess hydrazine hydrate are removed in vacuo and the 9 residue,6-ethyl-3-hydraZino-6H-pyrazolo[ 3,4- b ]thieno[ 2,3-dlpyridine-2-carboxylic acid ethyl ester is recrystallized fromdimethylsulfoxide, yield 2.1 g. (68%), m.p. 227229.

b. 6-ethyl-3-(isopropylidenehydrazino)-6H- pyrazolol 3.4-b]thieno[2,3-dlpyridine-L carboxylic acid, ethyl ester 1.5 g. of6-ethyl-3-hydrazino-6H-pyrazolo[3,4-b]-thieno[2,3-dlpyridine-2-carboxylic acid, ethyl ester, (0.005 mol.) arerefluxed in mljof acetone together with a few drops of acetic for 3hours. The acetone is distilled off and the residue, 6-ethyl-3-(isopropylidenehydrazino )-6H-pyrazolo[ 3,4-b]thieno[2.3-d]pyridine-2'carboxylic acid, ethyl ester, isrecrystallized from dimethylformamide, yield 0.9 g. (51%), m.p. 194-196.

EXAMPLE 4 6-Ethyl-3-phcnyl-6H-pyrazolo[ 3,4-b]thieno[ 2,3- d]pyridine-2-carboxylic acid a. S-benzoyl- 1 -ethyl-4-hydroxy- 1H-pyrazolol 3,4-

blpyridine 222 g. of S-amino-l-ethylpyrazole(2mol.) and 496 g. ofethoxymethylenebenzoylacetic acid ethyl ester (2 mol.) are heated withstirring to about 140 until no more alcohol distills. The temperature isthen raised to 240. The alcohol formed is distilled off in vacuo. Afterabout l hour the reaction is completed, the residue is cooled to roomtemperature and 500 ml. of methanol are added. S-Benzoyl- 1-ethyl-4-hydroxy- 1 H- pyrazolo[3,4-b]pyridine crystallizes and isfiltered off, yield 360 g. (67%), m.p. 151.

b. 5-benzoyl-4-chloro- 1 -ethyll H-pyrazolo[ 3,4-

blpyridine 5 3 .5 g. of benzoyll -ethyl-4-hydroxy-l H-pyrazolo[3,4-blpyridine (0.2 mol.) and 150 ml. of phosphorus oxychlorideare refluxed at 150 for 5 hours. The excess phosphorus halide is removedin vacuo and the residue neutralized with saturated sodium bicarbonatesolution. The pale yellow crystals of5-benzoyl-4-chloro-l-ethyl-1H-pyrazo1o[3,4-b]- pyridine are filtered offand recrystallized from ethyl acetate, yield 35 g. (61%), mp. 140

c. S-benzoyl-l-ethyl-4-(ethoxycarbonylmcthyl)thio- 1 H-pyrazolol3,4-b1pyridine 28.5 g. of 5-benzoyl-4-chloro- 1 -ethy1- 1 H-pyrazolo[3,4-b]pyridine (0.1 mol.), 12.5 g. of triethylamine and 12 g.of mercaptoacetic acid ethyl ester are heated with stirring in 150 ml.of dimethylformamide at 60 for 5 hours. The undissolved material isfiltered off and the filtrate treated with water.S-Benzoyl-lethyl-4-(ethoxycarbonylmethyl)thio-1H-pyrazo1o[3,4-blpyridine separates and is recrystallized from butanol. yield 28.2 g.(76%). m.p. 157160.

d 6-ethyl-3-phenyl-6H-pyrazolo[ 3,4-b ]thieno[ 2,3-

d]pyridine-2-carboxylic acid, ethyl ester 3.7 g. of S-bcnzoyll -ethyl-4-(ethoxycarbonylmethyl)-thio-1H-pyrazo1o[3.4- blpyridine (0.01 mol.) and0.24 g. of sodium hydride are refluxed for 5 hours in dry dioxane. Afterthis time, the solvent is distilled off and the residue, 6-ethyl-3-phenyl-6H-pyrazolol 3,4-b lthienol 2.3-d ]pyridine-2- carboxylic acid.ethyl ester. is recrystallized from butanol, yield 2.2 g. (63%), m.p.162164.

e. 6-ethyl-3-phenyl-6H-pyrazoloI 3.4- ]thienol 2.3-

d lpyridine-Z-carboxylic acid 3.5 g. of6-ethyl-3-phenyl-6H-pyrazolo13,4- blthienol2,3-dlpyridine-2-carboxylicacid, ethyl ester, (0.01 mol.) are treated with a solution of 1 g. ofpotassium hydroxide in 20 ml. of ethyl alcohol at 60 for 10 hours. Themixture is evaporated to dryness, the residue is dissolved in 20 ml. ofwater and acidified with acetic acid. The6-ethyl-3-phenyl-6H-pyrazolo[3,4- blthienol 2,3-dJpyridine-Z-carboxylicacid precipitates, is filtered off and recrystallized fromdimethylformamide, yield 2.1 g. (65%), m.p. 276278.

EXAMPLE 5 3-Ethoxy-6H-pyrazolo[ 3 ,4-b ]thieno[2,3-d]pyridine carboxylicacid and ethyl ester 4-Hydroxy- 1 -(2-furyl)methyl-1 ll-pyrazolo[3,4-b]- pyridine-5-carboxylic acid ethyl ester (produced as described inExample 56 of application serial no. 169,536, filed August 5, 1971) istreated in parts b through f of Example 1 to obtain 3-ethoxy-6-(2-furyl)methyl-6H-pyrazolo[3,4-b]thieno[2,3- dlpyridine-Z-carboxylic acid,ethyl ester. 0.1 mol. of this product and 20 g. of selenium dioxide(0.18 mol.) are suspended in ml. of diethyleneglycol dimethyl ether. Themixture is heated with stirring at and a few drops of water are added.The temperature is maintained for about 1 hour. After cooling, 100 m1.of water are added and the mixture is neutralized with dilute ammonia toobtain 3-ethoxy-6l-l-pyrazolo[3,4- b]thieno[2,3-dlpyridine-Z-carboxylicacid, ethyl ester. This product is hydrolyzed as in Example 1 g toobtain 3-ethoxy-6H-pyrazolo[3,4-b]thieno[2,3-dlpyridine-2 -carboxylicacid.

EXAMPLE 6 3-Phenyl-6H-pyrazolol 3 ,4-b]thieno[ 2,3-d lpyridine-Z-carboxylic acid and ethyl ester5-Benzoyl-4-hydroxy-1-(2-fury1)methyl-1H- pyrazolo[3,4-b]pyridine(produced as described in Example 5 of application serial no. 361,120,filed May 17, 1973) is treated as described in parts bthrough d ofExample 4 to obtain 6-(2-furyl)methyl-3-phenyl-6H-pyrazolol3,4-b]thieno[2,3-d]-pyridine-2-carboxylic acid, ethyl ester.This product is then treated with selenium dioxide and subsequentlyhydrolyzed as in Example 5 to obtain 3-phenyl-6H-pyrazolol3,4-blthienoI2,3-d]pyridine-2-carboxylic acid, ethyl ester, and the freeacid, respectively.

EXAMPLE 7 The following addition compounds are produced by the procedureof Example 1:

l l 12 R R. R2 R". 4

z r C2H5 CH, ()H G iC,,H C H H OQHTU) H CH CHr CH OH H 1. -r- C OC. ,H H

H CH (H OC. .H H

C H (H CH CH. OH CH CH3 cH cH. H OC-ZHF. l

3 H, C; H OH CH CH3 CH1. QIHZ OC H CH}:

z r, CH5 CH CH H z s Cg r, H NH. H

C (H;, H cr 3 H CH C. ,H H Cl-Q- H EXAMPLE 8 R 1 R.

By treating each of the products of Example 7 -u 2 5 2 5 NH t. H whereinR IS a lower alkoxy group by the procedure of Example 2 with butylamine,dimethylamine, diethylamme and ammonia, respectively, the followingadditional H products are obtained: 1 L

H CH I H cngcu H CH3 S (H;, CH3 C:\H7 CH3 EXAMPLE 9 ple 3, the followingproducts are obtained:

S-- C COOR H H H H H m. HHHHC EXAMPLE l() ing the hydrazines of Examples3a and 9 with the alde- 30 hyde or ketone in the first column, thefollowing prod- By following the procedure of Example 3b and utilizt arebt i ed;

HHHH

HHHH

C H C H What is claimed is: l. A compound of the formula ll c-R 2. Acompound as in claim 1 wherein R, R, and R each is hydrogen or loweralkyl, and R,, is lower alkyl, phenyl. hydroxy or lower alkoxy.

3. A compound as in claim 1 wherein R, R, and R each is hydrogen orlower alkyl, and R,, is phenyl, hydroxy or lower alkoxy.

4. A compound as in claim 1 wherein R and R, each is lower alkyl, R andR each is hydrogen.

5. A compound as in claim 4 wherein each lower alkyl group is ethyl andR;, is ethoxy.

6. A compound as in claim 4 wherein each lower alkyl group is ethyl andR is hydroxy.

7. A compound as in claim 4 wherein each alkyl group is ethyl and R isphenyl.

8. A compound as in claim 1 wherein R. R and R, each is hydrogen, and R,is hydrogen.

9. A compound as in claim 8 wherein R is ethoxy.

10. A compound as in claim 8 wherein R is phenyl.

1. A COMPOUND OF THE FORMULA
 1. A compound of the formula
 2. A compoundas in claim 1 wherein R, R1 and R2 each is hydrogen or lower alkyl, andR3 is lower alkyl, phenyl, hydroxy or lower alkoxy.
 3. A compound as inclaim 1 wherein R, R1 and R2 each is hydrogen or lower alkyl, and R3 isphenyl, hydroxy or lower alkoxy.
 4. A compound as in claim 1 wherein Rand R1 each is lower alkyl, R2 and R4 each is hydrogen.
 5. A compound asin claim 4 wherein each lower alkyl group is ethyl and R3 is ethoxy. 6.A compound as in claim 4 wherein each lower alkyl group is ethyl and R3is hydroxy.
 7. A compound as in claim 4 wherein each alkyl group isethyl and R3 is phenyl.
 8. A compound as in claim 1 wherein R, R2 and R4each is hydrogen, and R1 is hydrogen.
 9. A compound as in claim 8wherein R3 is ethoxy.